L-methylfolate is crucial to DNA synthesis and detoxifying homocysteine. It can also improve a variety of mental disorders including depression and schizophrenia.

Read on to see if you should be supplementing with L-methlyfolate.

What is L-Methylfolate?

Folate, otherwise known as vitamin B9, is one of the 13 essential vitamins. Vitamins come in different forms called vitamers that often need to be converted in the body to active forms of the vitamin. The active form of folate in the body is L-methylfolate, also known as levomefolic acid, which can cross both cell membranes and the blood-brain barrier [1].

A critical role of L-methylfolate is to act as a regulator of a class of neurotransmitters called monoamines. The three different neurotransmitters it helps make are [2]:

  • Serotonin
  • Dopamine
  • Norepinephrine

Folate can’t be synthesized by the body, so it must be ingested either through food or supplements [3].

The synthetic form of folate is folic acid, which can be found in fortified foods such as bread and cereals, and multivitamins [2, 4].

Dihydrofolate is the dietary form of folate and can be found in green vegetables, egg yolk, legumes, grains, nuts, some fruits, yeast, and organ meats like liver and kidneys [2, 4].

Both folic acid and dihydrofolate are converted into L-methylfolate in the body by a specific enzyme. It is then transported into the brain where it increases the production of the three neurotransmitters mentioned above [2].

Folic acid supplementation and unmetabolized folic acid have been associated with an increased incidence of prostate cancer, lower cognitive test scores, and smaller red blood cells [5, 6].

Methylfolate is responsible for many methylation reactions all throughout the body. Methylation reactions occur when methylfolate donates a methyl group (three hydrogens bonded to one carbon atom) to another molecule [4].

Methylation reactions are crucial for processes such as cell division and DNA and RNA synthesis. Methylation of DNA and RNA plays a crucial role in epigenetics, which is a change in gene activity without changes to the underlying genetics [7].

Although many people take L-methylfolate supplements, much of the naturally ingested L-methylfolate actually comes in the form of different folates such as folic acid and dihydrofolate [2, 4].

The conversion of these folates to L-methylfolate is crucial because L-methylfolate can cross the blood-brain barrier, while the other forms of folate can’t [4].

L-methylfolate is commonly used to slow cognitive decline that is seen in many mental disorders, including Alzheimer’s, mania, and depression. Many of these disorders are linked to mutations in the gene that produce the enzyme that converts folate into L-methylfolate, 5, 10-methylenetetrahydrofolate (MTHFR) [8, 9, 10, 4].

Mutations in MTHFR can lead to decreased methylfolate production. Mutations in MTHFR are very common and there are up to 30 different kinds of MTHFR mutation variations [4].

Mechanisms of Action

L-Methylfolate is responsible for:

  • Methylation [4]
  • DNA/RNA synthesis [7]
  • Conversion of homocysteine to methionine [4]
  • Homocysteine is a toxic amino acid that is particularly damaging to blood vessels (endothelial cells). High levels of homocysteine lead to increased inflammation and risk of coronary heart disease [4]
  • L-methylfolate methylates homocysteine into the less-toxic methionine, an essential amino acid [4]

L-Methylfolate Health Benefits

1) L-methylfolate Can Help Treat Depression

In a study (DB-RCT) of 123 patients with either depression or schizophrenia, a large portion of them had folate deficiencies [10].

Patients with folate deficiencies were given either methylfolate or placebo. The patients given methylfolate improved significantly compared to placebo both clinically and socially, especially in mood, and the difference in improvements increased with time [10].

In a study (DB-RCT) of 68 depression patients who did not respond to antidepressants (selective serotonin reuptake inhibitors, or SSRI), 15 mg/day of L-methylfolate was given for 12 months. Of the 68 patients, 26 had a full recovery from their depression and 35 experienced a reduction in the severity of their depression (remission) [11].

None of the patients who had a full recovery experienced a relapse or recurrence of their symptoms during the trial [11].

In one study, 147 patients given only SSRIs were three times more likely to become hospitalized than patients given SSRIs plus L-methylfolate supplements [12].

Depression can be caused by a number of different factors. This explains why certain drugs and supplements work for some people and not others. L-methylfolate supplementation is more effective in depression patients with these traits [2]:

  • Decreased levels of folate or any other folate by-products in the blood
  • Unresponsive to common antidepressants
  • Low folate levels as a result of:
    • Alcohol addiction
    • Eating disorders
    • Pregnancy
    • Gut disorders
    • High homocysteine levels
    • Drugs that interfere with folate metabolism

When homocysteine is converted to methionine by L-methylfolate, S-adenosylmethionine (SAM-e) concentrations rise. SAM-e is responsible for donating methyl groups to fat molecules that line our cell membranes and in the formation of the neurotransmitter serotonin [4].

L-Methylfolate Can Help Those with Bipolar 1 Depression

The Montgomery Asberg Depression Rating Scale (MADRS) is used to measure the degree of depression in patients with a higher score number being worse [9].

In a study of 10 patients with bipolar depression, L-methylfolate in combination with conventional treatment reduced the average MADRS score from 23.4 to 13.9 [9].

Six out of the 10 patients showed at least a 50% improvement in MADRS score and the other four experienced a reduction in the severity of their depression (remission) [9].

2) L-methylfolate Can Help With Schizophrenia

In a study of 91 schizophrenic patients, there was a link between the severity of the negative symptoms of schizophrenia and low blood levels of folate [13].

It was hypothesized that the link was due to poor diet and more cigarette smoking in schizophrenic patients [13].

Indeed, cigarette smoking was linked to decreased levels of folate [13].

In a study (DB-RCT) of 140 schizophrenic patients, only those given folic acid with vitamin B12 supplementation (and a specific mutation of the FOLH1 gene) improved negative symptoms considerably. The FOLH1 gene is one of the genes responsible for metabolizing methylfolate [14].

All the patients in the previously mentioned study had been on antischizophrenic drugs for six months prior or longer but had shown no improvements in symptoms [14].

In another study (DB-RCT) of 35 schizophrenic patients, L-methylfolate not only improved symptoms but also produced beneficial changes in the brain [15].

The patients given L-methylfolate supplements showed increased cortical thickness in the medial prefrontal cortex (mPFC), which was correlated to a partial restoration of structure and function of the mPFC [15].

The medial orbitofrontal cortex (mOFC), which normally deactivates during tasks requiring working memory, is dysfunctional in schizophrenic patients. The patients receiving L-methylfolate supplementation showed increased deactivation [15].

Schizophrenia can be due to many different factors. This is the reason why one of the studies only found positive effects in those with FOLH1 gene mutations [14].

3) L-Methylfolate Can Help With Alzheimer’s Disease

People with Alzheimer’s disease are more likely to have reduced folate levels compared to healthy people. Therefore, L-methylfolate supplements can improve symptoms in those patients [16].

Alzheimer’s disease is also brought about by increased inflammation in the brain due to higher levels of tumor necrosis factor (TNF)-α, an inflammatory molecule, and amyloid beta plaques. In a study (SB-RCT) of 121 patients, L-methylfolate greatly reduced levels of TNF-α and amyloid beta [16].

In a recent clinical trial of 30 Alzheimer’s and dementia patients, L-methylfolate greatly reduced brain deterioration in the hippocampus and cortical areas of the brain [8].

The conversion of homocysteine slowed brain deterioration and improved cognitive functions such as learning and memory [8].

The study indicated that treatment for at least one year is usually necessary to slow decline [17].

4) L-Methylfolate Can Reduce Mania

Mania is a state of heightened arousal, elevated mood, and increased energy.

The Young Mania Rating Scale (YMRS) is used to score mania with higher numbers signifying worse mania [9].

In a study of 10 manic and bipolar depressed patients, L-methylfolate reduced the average pre-treatment YMRS from 3.2 to 2.7 [9].

5) L-Methylfolate Improves Pregnancy Outcomes

L-methylfolate is crucial for pregnant women as it helps reduce the risk of developing different disorders that can occur in both the fetus and the mom. Because of the importance of supplementation, the U.S. government began mandating the addition of more folic acid into grain products (140µg/100g) in January 1998 [3, 18].

L-Methylfolate Supplementation can Help Prevent Neural Tube Defect (NTD)

L-Methylfolate supplementation helps prevent neural tube defect, which are defects of the brain, spine, and spinal cord [3].

It is advised for women that are more at risk for NTD to take 5mg daily and all other pregnant women to take 0.4-1mg daily [3].

L-Methylfolate Supplementation can Help Prevent Anemia

Pregnant women usually have reduced hemoglobin (protein that carries oxygen in the blood) levels, which leads to anemia in 5% of pregnancies [3].

In a study of 58 pregnant women taking prenatal supplements along with L-methylfolate had significantly higher hemoglobin levels at the time of delivery than 54 women only taking prenatal supplements [19].

L-Methylfolate May Prevent Preterm Birth

Low blood folate levels have been linked to shorter pregnancy times [3].

A study of 34,480 women found that supplementing with L-methylfolate for longer than one year significantly decreased the chances of preterm birth. The length of L-methylfolate supplementation (> 1 year) was equally as important as supplementing itself [3].


Supplementing with L-methylfolate has also been shown to reduce risks of other pregnancy problems such as heart defects and orofacial clefts, which are openings that may form in the mouth and lip [20, 21].

6) L-Methylfolate Can Boost the Immune System

T cells are key cells involved in the innate immune system, the part of the immune system that provides short-term defense against pathogens. A cell study showed that folate deficiency led to decreased production of T-cells [22].

Increasing folate levels increased the T-cell levels to normal levels [22].

Other studies have shown that deficiencies in folate also lead to decreased responses of T-cells and antibodies to certain pathogens. This ultimately leads to decreased resistance to infections [23].

7) L-Methylfolate May Improve Autism

Mutations in the gene encoding the enzyme 5,10-methylenetetrahydrofolate (MTHFR) disrupt the enzyme’s ability to convert folic acid into L-methylfolate. L-methylfolate decreased symptoms of aggressive and disruptive behavior in an autistic child with an MTHFR C667T mutation [24].

Further studies need to be done to validate these results.

Side Effects and Risks of L-Methylfolate

Common side effects of L-methylfolate include [9]:

  • dry mouth
  • fatigue
  • headaches

Overconsumption of L-methylfolate can mask vitamin B12 deficiencies [3].

L-Methylfolate Dosage

Many of the commercial L-methylfolate supplements contain between 5,000 mcg (5 mg) and 1,000 mcg (1 mg).

However, many studies have used doses of up to 15 mg to see intended effects [10].

Please consult your physician to determine the correct dosage to address your health issues.

Drug Interactions

1) Drugs That May Interfere with L-Methylfolate Absorption

Certain drugs can decrease folate levels leading to decreased L-methylfolate concentrations in the brain due to interfering with absorption. Some examples are listed below [4]:

  • Antacids
  • Alcohol
  • Oral contraceptives
  • Metformin
  • Some statin drugs
  • Anticonvulsants
    • Valproate
    • Carbamazepine
    • Phenytoin
    • Lamotrigine

A study done on 36 children taking Carbamazepine and 30 children taking Valproate showed that these medications reduced folic acid levels in the blood significantly [25].

The loss of folic acid led to significantly higher levels of homocysteine in the children taking Valproate and Carbamazepine [25].

2) L-Methylfolate Supplementation May Reduce the Effectiveness of Methotrexate

Methotrexate has been used to treat psoriasis, which is a disease that causes the formation of red patches on the skin with silver plaques and scales, for over 40 years [26].

However, methotrexate works by inhibiting dihydrofolate reductase (DHFR), an enzyme that metabolizes folic acid. Therefore, L-methylfolate supplementation can work to counteract the mechanisms by which methotrexate heals [26].

A case study on one patient taking both methotrexate for his psoriasis and L-methylfolate for his depression showed the patient developed psoriatic lesions after taking L-methylfolate. Only when the patient stopped taking methotrexate did the lesions disappear [26].

L-Methylfolate in Combination With Other Drugs and Supplements

1) L-Methylfolate Supplementation Enhances Effects of Antidepressants

A study comparing L-methylfolate plus selective serotonin reuptake inhibitors (SSRI, a common antidepressant) therapy (95 patients) with just SSRI therapy (147 patients) showed that adding L-methylfolate greatly enhanced results [12].

For instance, discontinuation rates for L-methylfolate plus SSRI were 17.9% compared to 34% for only SSRI therapy [12].

By 60 days, a major improvement was seen in up to 18.5% of patients on L-methylfolate plus SSRI patients while only 7% of patients on just SSRI showed improvements [12].

The time it took until major improvements showed was 177 days for the patients on L-methylfolate plus SSRI compared to 231 days for patients solely on SSRI [12].

The combined therapy also showed that patients were more likely to adhere to the therapy and there were fewer people that refused treatment due to lower rates of adverse events [12].

2) L-Methylfolate Supplementation with Vitamin B12 and N-acetylcysteine Delays Brain Deterioration in Alzheimer’s Disease

A study on 67 patients with Alzheimer’s disease showed that L-methylfolate supplementation with vitamin B12 and N-acetylcysteine significantly slowed deterioration in the brain [8].

3) L-Methylfolate Supplementation Improves the Beneficial Effects of Cholinesterase Inhibitors (ChI) in Alzheimer’s Patients

Cholinesterase inhibitors prevent the enzyme cholinesterase from breaking down the neurotransmitter acetylcholine.

In a study (DB-RCT) of 57 Alzheimer’s patients, folic acid supplementation was studied to see if it could boost the effects of ChI therapy [27].

The patients given both folic acid and ChI therapy significantly improved in performing daily living activities and in social behavior compared to patients only given ChI therapy [27].

4) L-Methylfolate Supplementation with Donepezil may Boost Effects on Those with Vascular Dementia

Folate supplementation along with Donepezil (used to treat Alzheimer’s disease) and natrium diethyldithiocarbamate trihydrate (NDDCT) greatly improved symptoms in those with vascular dementia [28].

The increased effects were seen in the areas of learning, memory, and endothelial dysfunction [28].

Contraindications of L-Methylfolate Supplements

The L-methylfolate can invoke an allergic response to those that are allergic to folic acid. This was experienced by one user in a review board.

Otherwise, there are no specific contraindications to L-methylfolate supplementation.

SNPs That Can Reduce L-Methylfolate Levels

The enzyme 5,10-methylenetetrahydrofolate (MTHFR) is responsible for the conversion of folate or folic acid into L-methylfolate. Mutations in the gene responsible for MTHFR creation lead to decreased L-methylfolate production [4].

Humans have two copies of each gene and different forms of the same gene are called alleles.

There are up to 30 different kinds of mutations in the MTHFR gene. Up to 60% of Americans carry at least one allele with a mutation in the MTHFR gene (heterozygous).

One common mutation is called C677T and it is prevalent in up to 10% of the white people and up to 22% of the Hispanics and Mediterranean populations. Having one allele with this mutation decreases MTHFR activity by up to 35%, while having two alleles with this mutation (homozygous) decreases activity by 70% [2914].

One male patient suffering from depression, mania, and obsessive-compulsive disorder (OCD) was screened and found with an MTHFR C677T mutation. Common medications were tried and failed to produce results. Only after L-methylfolate supplementation did the male patient showcase improvements [30].

Another common mutation called A1298C also reduces MTHFR activity [31]. Individuals with two alleles with this mutation show 68% reduced activity in the MTHFR enzyme [32].

Patients suffering from schizophrenia and bipolar disorder are even more likely than depressed patients to have MTHFR mutations [33].

Supplementing with L-methylfolate bypasses all MTHFR mutations and increases methylation reactions throughout the body [4].

Mutations in the FOLH1 gene can also result in reduced folate levels due to impaired absorption of folate in the gut [34].

L-Methylfolate User Reviews

A review of those taking L-methylfolate supplements found that it was most helpful for those that were taking the supplement for depression, folic acid deficiencies, and borderline personality disorder.

Some users liked the L-methylfolate because it produced fewer symptoms than other antidepressants such as Lexapro while others still complained about some symptoms such as dry coughs, blurred vision, and dizziness.

One user said that after getting a genetic test and finding out that he/she had a genetic mutation that lowered folate levels, taking L-methylfolate has been one of the most successful antidepressant treatments yet. The user had already tried up to 30 different antidepressants and liked this one the best.

Possibly undergoing genetic tests to see if your depression is caused by folate deficiencies could be a good place to start to see whether or not L-methylfolate supplements are right for you.

Other sites have had mixed reviews as well with many people either very for the supplement or completely against it.

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